researcharticle cost-effectivenessofantivenomsfor...

RESEARCH ARTICLE

Cost-Effectiveness of Antivenoms forSnakebite Envenoming in 16 Countries inWest AfricaMuhammad Hamza1, Maryam A. Idris1, Musa B. Maiyaki1, Mohammed Lamorde2, Jean-Philippe Chippaux3, David A. Warrell4, Andreas Kuznik1,2,5, Abdulrazaq G. Habib1*

1 College of Health of Sciences, Bayero University, Kano, Nigeria, 2 Infectious Diseases Institute, MakerereUniversity College of Health Sciences, Kampala, Uganda, 3 Institut de Recherche pour le Development,Cotonou, Benin Republic and Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie, Paris,France, 4 Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, 5 CelgeneCorporation, Warren, New Jersey, United States of America

* [email protected]

Abstract

Background

Snakebite poisoning is a significant medical problem in agricultural societies in Sub Saha-

ran Africa. Antivenom (AV) is the standard treatment, and we assessed the cost-effective-

ness of making it available in 16 countries in West Africa.

Methods

We determined the cost-effectiveness of AV based on a decision-tree model from a public

payer perspective. Specific AVs included in the model were Antivipmyn, FAV Afrique, Echi-

Tab-G and EchiTab-Plus. We derived inputs from the literature which included: type of

snakes causing bites (carpet viper (Echis species)/non-carpet viper), AV effectiveness

against death, mortality without AV, probability of Early Adverse Reactions (EAR), likelihood

of death from EAR, average age at envenomation in years, anticipated remaining life span

and likelihood of amputation. Costs incurred by the victims include: costs of confirming and

evaluating envenomation, AV acquisition, routine care, AV transportation logistics, hospital

admission and related transportation costs, management of AV EAR compared to the alter-

native of free snakebite care with ineffective or no AV. Incremental Cost Effectiveness

Ratios (ICERs) were assessed as the cost per death averted and the cost per Disability-

Adjusted-Life-Years (DALY) averted. Probabilistic Sensitivity Analyses (PSA) using Monte

Carlo simulations were used to obtain 95% Confidence Intervals of ICERs.

Results

The cost/death averted for the 16 countries of interest ranged from $1,997 in Guinea Bissau

to $6,205 for Liberia and Sierra Leone. The cost/DALY averted ranged from $83 (95% Con-

fidence Interval: $36-$240) for Benin Republic to $281 ($159–457) for Sierra-Leone. In all

cases, the base-case cost/DALY averted estimate fell below the commonly accepted

PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0004568 March 30, 2016 1 / 16

OPEN ACCESS

Citation: Hamza M, Idris MA, Maiyaki MB, LamordeM, Chippaux J-P, Warrell DA, et al. (2016) Cost-Effectiveness of Antivenoms for SnakebiteEnvenoming in 16 Countries in West Africa. PLoSNegl Trop Dis 10(3): e0004568. doi:10.1371/journal.pntd.0004568

Editor: H Janaka de Silva, University of Kelaniya,SRI LANKA

Received: October 19, 2015

Accepted: March 2, 2016

Published: March 30, 2016

Copyright: © 2016 Hamza et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.

Data Availability Statement: All relevant data arewithin the paper and its Supporting Information files.

Funding: The authors received no specific fundingfor this work.

Competing Interests: At the time of the analysis, AKwas employed by Celgene Corporation, withownership of stock in Celgene Corporation.

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threshold of one time per capita GDP, suggesting that AV is highly cost-effective for the

treatment of snakebite in all 16 WA countries. The findings were consistent even with varia-

tions of inputs in 1—way sensitivity analyses. In addition, the PSA showed that in the major-

ity of iterations ranging from 97.3% in Liberia to 100% in Cameroun, Guinea Bissau, Mali,

Nigeria and Senegal, our model results yielded an ICER that fell below the threshold of one

time per capita GDP, thus, indicating a high degree of confidence in our results.

Conclusions

Therapy for SBE with AV in countries of WA is highly cost-effective at commonly accepted

thresholds. Broadening access to effective AVs in rural communities in West Africa is a

priority.

Author Summary

Antivenom is the main intervention against snakebite poisoning but is relatively scarce,unaffordable and the situation has been compounded further by the recent cessation ofproduction of effective antivenoms and marketing of inappropriate products. Given thiscrisis, we assessed the cost effectiveness of providing antivenoms in West Africa by com-paring costs associated with antivenom treatment against their health benefits in decreas-ing mortality. In the most comprehensive analyses ever conducted, it was observed theincremental cost effectiveness ratio of providing antivenom ranged from $1,997 in GuineaBissau to $6,205 for Liberia and Sierra-Leone per death averted while cost per DisabilityAdjusted Life Year (DALY) averted ranged from $83 for Benin Republic to $281 forSierra-Leone. There is probability of 97.3–100% that antivenoms are very cost-effective inthe analyses. These demonstrate antivenom is highly cost-effective and compares favor-ably to other commonly funded healthcare interventions. Providing and broadening anti-venom access throughout areas at risk in rural West Africa should be prioritized given theconsiderable reduction in deaths and DALYs that could be derived at a relatively smallcost.

IntroductionSnakebite poisoning is a significant cause of death and disability in rural West Africa[1,2,3,4,5,6,7]. The exact burden of snakebite is difficult to ascertain and is often undere-ported. A study by Jean-Philippe Chippaux reported an estimate of over 314, 000 envenom-ations, 7300 mortality and nearly 6000 amputations occurring yearly in sub-Saharan Africa(SSA) [7]. However, even in West Africa alone, a range of 1504 to 18,654 annual mortalityfrom snakebite envenoming has been made [8]. This is further compounded by the variabil-ity in snakebite incidence with estimates of as high as 500 bites per 100,000 persons per yearin parts of northern Nigeria [9].

Vipers (Echis ocellatus, E. leucogaster and E. jogeri) are a major cause of snakebite envenom-ing throughout the sub-region mainly in Benin republic, Burkina Faso, Cameroun, Chad,Gambia, Ghana, Mali, Niger, Nigeria, Togo and Senegal [1,2,3,4,5,6,7]. In the sub-region,envenoming from snakes other than vipers mostly results from African spitting cobras (Najanigricollis, N. katiensis), puff-adder (Bitis arietans), mambas (Dendroaspis viridis, D. polylepis),

Cost-Effectiveness of Antivenoms for Snakebite in West Africa


burrowing asps or stiletto snakes (Atractaspis species), night adders (Causus maculatus, C.rhombeatus, C. resimus, C. lichtensteinii) and very rarely boomslang (Dispholidus typus).Joger’s carpet viper (E. jogeri) is confined to Mali. Romane’s carpet viper (Echis leucogaster)and Egyptian cobras (Naja haje and N. senegalensis) are causes of snakebite envenoming in theSahelian and drier parts of West Africa while the forest cobra (Naja melanoleuca) and the Gab-oon viper (Bitis gabonica) cause occasional bites in the rain forest and South-eastern parts ofthe sub-region [1,5,7].

In West Africa, carpet vipers may account for as many as two thirds of all snakebite enven-oming although their range is limited to the savannah region [1,9,10,11]. Envenoming fromcarpet vipers leads to swelling and tissue damage at the site of bite, local and systematic bleed-ing, anaemia and shock. Often death results from cerebral haemorrhage, bleeding elsewhere orhaemorrhagic shock [1,10,11]. The bleeding abnormality results from a prothrombin activatingmetalloprotease “Ecarin” and a FX activating component, an anticoagulant, platelet activator/inhibitor and haemorrhagins in the snake’s venom [1,10,11]. Non-clotting blood detected bythe 20minute Whole Blood Clotting Test [20WBCT] virtually confirms carpet viper envenom-ing in the northern third of Africa (roughly north of the equator) and is utilized to assess ade-quacy of treatment [1,10,11]. Most non-carpet viper bites lead to local swelling and tissuedamage. The colubrids, boomslangs and twig snake (Thelotornis kirtlandii), are back fangedsnakes that rarely envenom but can cause severe bleeding and acute kidney injury. Neurotoxicfeatures may result from Naja haje, Naja melanoleuca and Dendroaspis spp bites with deathsoften resulting from respiratory muscle paralysis [12]. The risk of death from snakebites otherthan viper envenoming is lower [9,13,14,15,16,17], but cobra spits may lead to blindness andbites to cancerous ulcers, abortions, scarring, arthrodeses, contractures and psychologicalimpairment leading to permanent disability and productivity loss following hospitalization andincapacitation [7,18,19,20,21]. Cessation of bleeding abnormalities and restoration of clottingfollowing administration of effective antivenom usually occurs promptly in carpet viper enven-oming. Antivenom is efficacious in decreasing the likelihood of dying and is the main treat-ment for snakebite envenoming [1,11,22,23]. However, its administration is associated withearly adverse reactions (EAR) which rarely results in fatality.[24,25,26]. Specific interventionsmay be required to either prevent EAR with administration of premedication prior to anti-venom or to treat it once developed following antivenom administration [25,26]. Antivenomsare formulated as either liquid agents that needs to conveyed and stored at low temperaturewith a life span of about three years [27,28] or as freeze dried substances that are more stablewith extended shelf life. Both types of formulations have been produced for the sub-region[6,27,28]. The average cost per treatment of antivenom was reported as US$124 (range US$55–$640) although a median price of US$153 was also reported for Sub-Saharan Africa [29,30,31].The few effective antivenoms in the sub-region generally have been scarce, locally unaffordableand inaccessible where they are most needed. Partly for these reasons antivenom utilizationhas drastically declined to a very small fraction of indicated need. The situation has been com-pounded further by the recent announcement by Sanofi-Pasteur that production and distribu-tion of FAV Afrique, currently the most widely distributed and most dependable antivenom inthe sub-region, will be discontinued by 2016. Its loss will exacerbate an already serious publichealth crisis and makes the management of snakebite even more challenging [32]. It is there-fore extremely important within the context of other competing public health priorities toassess the health economics of antivenoms to guide policy. Before the recent publication of ourwork focusing on Nigeria [33], few economic evaluations of preliminary nature had been con-ducted on antivenoms [34,35]. Here, we evaluated the cost-effectiveness of antivenom utility inthe treatment of snakebite envenomation by computing incremental cost effectiveness ratios(ICERs) of the cost per death averted and the cost per DALY averted by adapting a previously



published model for Nigeria to 16 countries in WA. We performed the analysis from health-care system perspective to provide policy makers with evidence towards broadening access toantivenoms given their importance in preventing loss of lives and limbs among poor vulnerablecommunities in West Africa.

Materials and Methods

Model OverviewA decision analytic model (Fig 1) was adapted to estimate health outcomes and costs associatedwith the availability and use of geographically appropriate and effective antivenoms for snake-bite poisoning in West Africa [33]. Details of the model structure are described elsewhere [33].Briefly, the model assessed the availability of effective antivenoms relative to no availability inthe decision node. The model differentiated snakebite envenoming by carpet viper and non-carpet viper and distinction was made on the basis of the 20WBCT in the treatment arm of themodel. Evidence of coagulopathy would lead to the administration of mono-specific antivenomthat neutralizes carpet viper venom only, whereas absence of coagulopathy triggers the admin-istration of a polyspecific antivenom that neutralizes venoms from several snakes, includingthe carpet viper. In the first chance node, the model included EARs associated with antivenomuse, which are more likely to occur with polyspecific rather than the monospecific antivenom[23,27,28,36,37]. Symptoms of EAR were diverse and death could happen in about 1% of cases[24,25,26]. Survivors of snakebite may recover completely or remain with significant sequaela(e.g. amputation) that was considered in the model. Treatment outcomes were converted intoDALYs on the basis of local life expectancy. Tree Age Pro Suite Healthcare 2014 software wasused for analyses.

Model InputsAntivenom effectiveness and Early Adverse Reactions (EAR) data. The likelihood of

death from carpet viper and other snakebites among untreated victims was previously reportedat 8.1–15.83% and 5–27.3% respectively [9,10,38,39,40,41,42] although these were varied insensitivity analyses. When data on antivenom effectiveness was available for a given country,it was applied for that country. It ranged from 56.43% to 92% against carpet viper deaths. Ameta-analysis estimate was applied for countries without data (Table 1) [38,39,40]. Therehasn’t been placebo-controlled randomized controlled trials (RCT) ever conducted for anti-venom assessment and the estimates of effectiveness derived from the meta-analysis that exclu-sively only included observational studies from Chad, Ghana and Nigeria [10,22,37,38,39] wereapplied in the model. Results from the meta-analysis suggested that an effective antivenom hasa 75% (95% confidence interval: 55–86%) effectiveness in averting mortality from carpet viperbites [22]. Since the meta-analysis included studies wherein polyspecific antivenoms were used,these estimates of effectiveness were applied against non-carpet viper deaths except in Beninand Guinea-Conakry, where country-level effectiveness data exists for Antivipmyn antivenomagainst non-carpet viper (elapid) deaths, reported at 43.6% (0–80.5%) (Table 1) [42]. However,in a scenario analysis antivenoms were assumed to be ineffective (0%) against non-carpet viperenvenoming. Estimates of EAR for the corresponding antivenoms were Antivipmyn 3.3% andFAV Afrique 4.3% as obtained in observational studies while it was EchiTab-G 19% and Echi-Tab-Plus 26% [23,36,37]. For countries where none of the antivenoms have been in use, theEAR risk median estimate of 4.3% was used in the model [36]. The EAR estimates were variedfrom 0% to 30% in sensitivity analyses. The risk for disability (limb amputation) among survi-vors was approximated to 3% from studies in sub-Saharan Africa and the tropics [7,43,44]. Inbase-case analysis antivenom administration had no effect on amputation, however,



Fig 1. Decision tree model for managing snakebite envenoming with or without FAV Afrique antivenom in Cameroun (each of the 16 countries hasa similar model with its data input).Model parameter definitions: c20WBCTest = cost of 20 minutes Whole Blood Clotting Test on 10 occassions over 7days at diagnoses and monitoring; cAdvReaction = Cost of managing early adverse reactions; cAntivenom = Cost of Antivenom; cFeed_Transp = Cost oftransporation and stay in Hospital for 7days; cRefrg_Transp = Cost of shipping and refrigeration; cNoAntivenom = Cost of management without effectiveantivenoms either traditional/herbal care or other alternatives; cSupp_care = Cost of supportive care. All costs are in US$. antivenomeff = Effectiveness of



effectiveness was applied in sensitivity analyses. The mean ages of snakebite envenomed vic-tims were reported for Chad 25.2 years, Niger 29 years, Nigeria 26 years and Mali 28 years[38,39,41,45,46]. So, since snakebite envenoming occurs among persons with average age inthe 25–29 year age group, we determined the remaining local life expectancies in this age groupfor the 16 countries ranged from 37 years in Sierra-Leone to 45 years in Ghana and Senegal(Table 1) [47]. The base-case analysis on disability was restricted to extremity amputationalthough blindness from venom-ophthalmia and Post Traumatic Stress Disorder (PTSD)from encountering snake with respective disability weights of 0.552 and 0.105 [48] were alsoexplored in scenario analyses. An annual discount rate of 3% was applied on the health out-comes (mortality and amputation) and the associated amputation-related disability weightused was 0.102 [48]. The model was adapted to 3 types of antivenoms used in WA: Antivipmynin Benin and Guinea Conakry; EchiTab-G and EchiTab-Plus in Burkina Faso and Nigeria;FAV Afrique in Cameroun, Chad, Ghana and Mali. For the remaining 8 countries without evi-dence of effectiveness data for a particular antivenom, the meta-analytic estimates were used[22]. Where other required data item was unavailable, data from adjacent or neighboring coun-tries were used to input a model with mixed data sources. These parameters for the respectivemodels were obtained in the literature and imputed to the antivenom-defined models and wasrun for each of the 16 countries.

Cost data. The cost of the full antivenom treatment regimen was modeled as US$153[29,30,31]. The cost of care, ten 20WBCT measurements in 7 days, transportation to-and-fromhospital and feeding for 7 days, shipping and freezing of antivenom, management of EAR, sup-portive care (such as pain relief, blood transfusion, medications, fluid replacement and woundmanagement) were obtained from series of envenomed patients admitted to Kaltungo GeneralHospital in Nigeria Table 2 [33]. All costs were expressed in US$. Given snakebite is a shortterm condition and costs occur during a brief period of time (2 to 10 days), costs were not dis-counted to adjust for time elapsed between expenditure and outcome during Incremental CostEffectiveness Ratio (ICER) calculations [49,50]. As a conservative analysis the alternative of noantivenom therapy carried a cost of zero as no treatment, care, test and EAR management wasprovided. However, in a scenario analysis cost of $65.63 was added/incurred for the alternativeof no antivenom therapy, comprising of supportive care $18.75, feeding and transportation$43.75, and for 20WBCT $3.125. The ICER was computed by dividing total cost by the differ-ence in DALYs (e.g., cost/DALY averted) [49,50].

Sensitivity analysis. One-way sensitivity analysis was performed for select input variablesto test robustness and determine the most important variables influencing cost-effectivenessof an antivenom programme. Each base-case model input was varied independently accordingto the upper and lower limits obtained from literature and according to low and high valuescenarios.

In addition, Probablistic Sensitivity Analyses (PSA) were performed using Monte Carlo sim-ulation by running 10,000 iterations of the model while randomly selecting the values for 16key model inputs from a probability distribution that was defined for each of the parameters(Table 2). This process enabled us to estimate the 95% confidence interval around the base caseICER estimates for each of the 16 countries included in the analysis, and it also allowed us toestimate the probability that antivenom therapy is cost-effective by calculating the proportion

antivenom to prevent death; pEARmono = probability of early adverse reactionswith monospecific antivenom; pEARpoly = probability of early adversereactionswith polyspecific antivenom; pEARmort = probability of dying following effective antivenom and early adverse reactions; pCVmort = probability ofdying following carpet viper envenoming; pNCVmort = probability of dying following non-carpet viper envenoming; pCV = proportion of envenoming due tocarpet viper; pDisabl = probability of disability; dw = disability weighting of consequences of snakebite envenoming; x = effect of adrenaline premedicationreduction of risk of early adverse reactions.

doi:10.1371/journal.pntd.0004568.g001



Table 1. Data estimates used in the model by country.

(a) Mean age atbite(+remaininglife expectancy[2012]), years

(b) Proportionof envenomingdue to CV orvipers (%)

(c)UntreatedMortality(CV; Non-CV)

(d)Mortalitypost AV(CV; Non-CV)

AV effectivenessagainst mortality(e) = [1-RR] oralternatively = (c-d)/c (for CV; Non-CV)

Risk of EarlyAdverseReactionswith CV(mono) andNCV(poly[(%)

Comments References

Model 1: Antivipmyn Antivenom

BeninRepublic

25–29 (44) 85% 15%; 9/33(27.3%)

3.11%; 4/26(15.4%)

79.3%; (NA)43.6% (0–80.5%)

3.3% Used NCVdata fromGuinea

Fayomi et al 2002[4]; Chippaux et al2007 [6]; Baldeet al 2012 [37];Balde et al 2013[42];

Guinea-Conakry

25–29 (43) 83% 15%; 9/33(27.3%)

3.11%; 4/26(15.4%)

79.3%; (NA)43.6% (0–80.5%)

3.3% Used CVdata fromBenin

Fayomi et al 2002[4]; Chippaux et al2007 [6]; Baldeet al 2012 [37];Balde et al 2013[42]; Adehossiet al 2011 [45];

Model 2: EchiTab-G and EchiTab-Plus Antivenom

Nigeria 26 (41) 66% 19/120(15.83%);5%

78/6137(1.27%)

92% (87–95%) ET-19%;ETPlus-26%

Warrell et al 1977[10]; Abubakaret al 2010[23];Habib &Abubakar 2011[38]; Pugh et al1980 [13]

BurkinaFaso

25–29 (43) 85% 12.1%; 5% NA 92% (87–95%) ET-19%;ETPlus-26%

Used AVeffect fromNigeria;Ghanamortality

Warrell et al 1977[10]; Abubakaret al 2010[23];Habib &Abubakar 2011[38]; Visser et al2008 [40]; Pughet al 1980 [13]

Model 3: FAV Afrique Antivenom

Cameroon 25–29 (41) 85% 15/98(15.3%)

NA 85.2%(56.1–95%); 4.3% Used (c) &(e) fromChad/Ghana

Chippaux et al1999 [36];Bregani et al2006 [39]; Visseret al 2008 [40];

Chad 25.2 (38) 85% 15/98(15.3%)

4/60(6.67%)

56.43% (0–85.2%); 4.3% Chippaux et al1999 [36];Bregani et al2006 [39];

Ghana 25–29 (45) 85% 8/66(12.1%); -

5/278(1.8%)

85.2%(56.1–95%); 4.3% Chippaux et al1999 [36]; Visseret al 2008 [40];

Mali 28 (43) 85% 8.1%; 5% 1.5% 81.48% (NA) 4.3% Chippaux et al1999 [36]; Drameet al 2012 [41]

Other/Multiple Antivenoms

Coted’Ivoire

25–29 (39) 83% 12.1%;- 75%(55–86%)- 4.3% AV efficacyfrom meta-analysis

Habib & Warrell2013 [22];Chippaux et al1999 [36]; Visseret al 2008 [40];

(Continued)



of 10,000 iterations that resulted in ICERs that fell below commonly accepted cost-effectivenessthresholds of one time per capita Gross Domestic Product (GDP) for each of the 16 countries[51,52].

The study reporting was done consistent to standard guidelines for cost effectiveness analy-ses and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) state-ment [49,50,52,53,54].

ResultsThe cost/death averted for the 16 countries of interest varied. It was as low as $1,997 in GuineaBissau to as high as $6,205 in Liberia and Sierra Leone. The cost/DALY averted ranged from alow of $83 (95% Confidence Interval: $36-$240) for Benin Republic to a high of $281 ($159–457) for Sierra-Leone. In all cases, the base-case cost/DALY averted estimate fell below the

Table 1. (Continued)

(a) Mean age atbite(+remaininglife expectancy[2012]), years

(b) Proportionof envenomingdue to CV orvipers (%)

(c)UntreatedMortality(CV; Non-CV)

(d)Mortalitypost AV(CV; Non-CV)

AV effectivenessagainst mortality(e) = [1-RR] oralternatively = (c-d)/c (for CV; Non-CV)

Risk of EarlyAdverseReactionswith CV(mono) andNCV(poly[(%)

Comments References

Gambia 25–29 (44) 40% 14.3% 75%(55–86%) 4.3% Enwere et al 2000[3]; Habib &Warrell 2013 [22];Chippaux et al1999 [36];

Guinea-Bissau

25–29 (41) 40% 15%; 27.3% 75%(55–86%);43.6% (0–80.5%)

4.3% Habib & Warrell2013 [22]; Baldeet al 2013 [42];Adehossi et al2011 [45];

Liberia 25–29 (44) 0% (*1%) 0%(*15%);5%

75%(55–86%) 4.3% Pugh et al 1980[13] Habib &Warrell 2013 [22];

Niger 29 (44) 85% 15%; 5% 75%(55–86%) 4.3% Habib & Warrell2013 [22];Chippaux et al1999 [36]; Fayomiet al 2002 [4];Adehossi et al2011 [45];

Senegal 25–29 (45) 40% 15%;5% 75%(55–86%) 4.3% Trape et al 2002[5];Habib &Warrell 2013 [22];Chippaux et al1999 [36];Adehossi et al2011 [45];

Sierra-Leone

25–29 (37) 0% (*1%) 0%(*15%);5%

75%(55–86%) 4.3% Pugh et al 1980[13] Habib &Warrell 2013 [22];

Togo 25–29 (43) 85% 12.1%; 5% 75%(55–86%)— 4.3% Habib & Warrell2013 [22]; Visseret al 2008 [40];

CV—carpet viper; RR—Relative Risk

doi:10.1371/journal.pntd.0004568.t001



commonly accepted threshold of one time per capita GDP, suggesting that AV is highly cost-effective for the treatment of snakebite in all 16 WA countries [51,52].

The findings from the analyses were also consistent to variations of inputs in 1-way sensitiv-ity and scenario analyses as depicted (Table 3 and Fig 2). The individual countries’modelresults were most sensitive to effectiveness of antivenom in decreasing mortality, natural (unat-tended) mortality, costs of antivenoms and types of snake causing envenoming (Fig 2). Resultswere not sensitive to antivenom associated EAR or the cost of managing it. Varying the costof antivenom from $125 to two times for victims who may require two doses, i.e. $306, stillyielded ICER estimates that remain cost-effective. The ICERs rose when the frequency ofsnakebite envenomation due to saw-scaled viper was reduced to 0% except in Benin andGuinea Conakry where Antivipmyn antivenom is used and is effective even against elapids(Table 3) [42].

Moreover, the ICER ranged from $97.26 in Benin to high levels of $13,964.26 in Liberia and$15,278.99 in Sierra Leone even in the worst case scenario where (poly-specific) antivenomshave nil effectiveness (0%) against bites from snakes other than carpet viper. These estimatesfall outside the cost-effectiveness thresholds in Liberia and Sierra Leone largely because non-carpet viper accounts for 99% of SBE. Applying a modest reduction of 40% on the probabilityof EAR with the use of adrenaline premedication [25,26,33] gave a cost per DALY avertedslightly lower than base-case ICERs. Similarly, the ICERs were only very slightly altered evenwhen more serious or more frequent disabilities were substituted in the model. This was dem-onstrated with venom-induced-blindness (0.01%) or Post-Traumatic-Stress-Disorder (20%)with disability-weights of 0.552 and 0.105 respectively [18,21,48].

Furthermore, our PSA confirms the model findings remain consistent to concurrent varia-tion of all model inputs, as the ICERs with their respective 95% confidence limits are far lessthan the cost-effectiveness thresholds (Table 3). It showed that in majority of simulations(97.3% in Liberia to 100% in Cameroun, Guinea Bissau, Mali, Nigeria and Senegal (Fig 3)) our

Table 2. General assumptions used in Monte Carlo simulations.

Assumption Base Case Value (BCV) Range of BCVs Distribution Reference

Proportion of envenoming due to CV/ Non-Elapids (%) Varies by country 1–85% Beta 1,5,6,7,36

Mortality due to untreated CV envenoming (%) Varies by country 8.1–15.83% Beta 3,4,10,39,40,41,45

Mortality due to untreated Non-CV/Elapid envenoming (%) Varies by country 5–27.3% Beta 13,14,42

AV effectiveness against CV mortality (%) Varies by country 56.43–92% Beta 4,6,10,22,38,39,40,41

AV effectiveness against Non-CV/Elapid mortality (%) Varies by country 43.6–92% Beta 10,38,42

Risk of AV EAR for CV envenoming (%) Varies by country 3.3–19% Beta 23,36,37

Risk of AV EAR for Non-CV envenoming (%) Varies by country 3.3–26% Beta 23,36,37

Risk of AV EAR mortality (%) 1% Same for each country Beta 24

Risk of amputation following envenoming (%) 3% Same for each country Beta 7,43,44

Disability weight for amputation 0.102 Same for each country Beta 48

Cost of antivenom (US$) $153 Same for each country Normal 29,30,31

Cost of 20min Whole Blood Clotting Test $3.125 Same for each country Normal 33

Cost of managing Early Adverse Reactions $1.875 Same for each country Normal 33

Cost of supportive care $18.75 Same for each country Normal 33

Cost of feeding and transportation $43.75 Same for each country Normal 33

Cost of refrigeration and transportation $18.75 Same for each country Normal 33

Cost of no antivenom (US$) $0 Same for each country Not varied Our assumption

DALYs averted per death averted (3% discounted) Varies by country 22.17–24.52 Not varied Our calculations

DALYs averted per amputation averted (3% discounted) Varies by country 2.26–2.50 Not varied Our calculations




Table 3. Results frommodel outputs by country and scenarios.

Country andGDP/Capita($) [49]

Increm CostEffect Ratio[ICER]/DALY($) (95%Conf.Interval)

Cost/DeathAverted($)

ProbabilityAntivenom iscost-effective(%)

ICER ifAntivenomCost = $125

ICER ifAntivenomCost = $306

ICER ifproportion ofCarpetViper = 0% ($)

ICER if AvEffect for NonCarpetViper = 0% ($)

ICER if the ‘NoAntivenom’ armpaid for Basiccosts of $65.63*

Benin (751) 82.63 (36.41–240.09)

1997.91 99.99 72.87 135.96 81.75 97.26 59.75

B/Faso (652) 99.44 (40.39–377.40)

2384.81 99.61 87.98 164.05 226.53 107.18 71.94

Cameroun(1220)

86.97 (38.47–240.43)

2030.05 100.00 76.70 143.11 238.39 92.01 62.89

Chad (1035) 136.94(51.33–704.75)

3070.80 99.13 120.77 225.34 376.61 144.89 99.03

Cote d’Ivoire(1366)

128.24(51.20–461.64)

2916.02 99.97 113.09 211.04 278.37 139.16 92.73

Gambia(509)

150.08(72.18–305.49)

3628.88 99.99 132.25 247.47 261.77 229.59 108.30

Ghana(1646)

103.61(42.04–372.87)

2532.73 99.99 91.38 170.50 227.63 111.21 74.93

GuineaBissau (576)

87.09 (44.96–171.55)

2032.72 100.00 76.75 143.60 84.76 226.64 62.85

GuineaConakry(493)

83.54 (36.59–236.35)

1997.41 99.98 73.67 137.49 82.68 100.72 60.40

Liberia (414) 256.61(147.67–417.68)

6204.95 97.28 226.00 423.92 261.77 13,964.26 184.85

Mali (696) 160.48(82.21–306.83)

3836.74 100.00 141.52 264.06 243.47 178.09 116.04

Niger (385) 97.23 (39.84–328.02)

2351.06 98.64 85.75 159.99 261.77 102.98 70.31

Nigeria(2742)

92.56 (40.27–242.63)

2160.33 100.00 81.61 152.35 232.04 107.96 66.91

Senegal(1023)

143.81(67.34–317.76)

3515.25 100.00 126.73 237.14 258.95 216.41 103.78

Sierra Leone(590)

280.77(158.51–456.68)

6204.95 99.86 247.27 463.83 286.42 15,278.99 202.25

Togo (589) 120.42(47.62–455.04)

2878.98 98.86 106.19 198.14 264.75 129.25 87.08

*Scenario of Basic costs in the No antivenom arm = Cost of supportive care ($18.75) + Cost of feeding and transportation ($43.75) + Cost of 20min Whole

Blood Clotting Test ($3.125) = $65.63

AV—antivenom; ICER—Incremental Cost Effectiveness Ratio;




model results yielded an ICER that fell below the threshold of one time per capita GDP, thus,indicating a high degree of confidence in our results [51,52].

DiscussionEconomic modeling is very useful in determining the best ways to utilize resources to optimallymanage medical conditions where there are competing priorities and limited resources [49].This is the first extensive assessment of the cost-effectiveness of expanding antivenom access inthe 16 countries in West Africa. We find that the cost/death averted for the 16 countries ofinterest ranged from $1,997 in Guinea Bissau to $6,205 for Liberia and Sierra Leone. The cost/DALY averted ranged from $83 (95% Confidence Interval: $36-$240) for Benin Republic to$281 ($159–457) for Sierra-Leone. The ICER point estimate is<$100/DALY averted in 7 coun-tries, $100-$200/DALY averted in 7 countries and<$300/DALY averted in 2 countries. Theresults show that snakebite antivenoms are highly cost-effective in West Africa, as our findingsare far less than the one time per capita GDP threshold [51,52]. While it will be worthwhile torepeat the analysis for similar geographic and socioeconomic settings, most of the model inputssuch as the antivenom efficacy and cost would largely be similar across many African countries

Fig 2. Tornado diagrams assessing the impact of changes in envenoming/antivenom and cost parameters on the incremental cost-effectivenessratio (ICER) per DALY for antivenom use in Guinea Bissau (L) and Senegal (R). Diagram parameter definitions: c20WBCTest = cost of 20 minutesWhole Blood Clotting Test on 10 occassions over 7 days at diagnoses and monitoring; cAntivenom = Cost of Antivenom; cFeed_Transp = Cost oftransporation and stay in Hospital for 7days; cRefrg_Transp = Cost of shipping and refrigeration; cNoAntivenom = Cost of management without effectiveantivenoms either traditional/herbal care or other alternatives; cSupp_care = Cost of supportive care. All costs are in US$. Antivenomeff = Effectiveness ofantivenom to prevent death; pEARmono = probability of early adverse reactions with monospecific antivenom; pEARpoly = probability of early adversereactionswith polyspecific antivenom; pEARmort = probability of dying following effective antivenom and early adverse reactions; pCVmort = probability ofdying following carpet viper envenoming; pNCVmort = probability of dying following non-carpet viper envenoming; pCV = proportion of envenoming due tocarpet viper; pDisabl = probability of disability.




with similar GDPs where snakebite envenoming occurs. An exception may be the prevalenceof carpet viper (Echis ocellatus) envenoming, a snake that is confined to West Africa extendingeastwards only as far as Chad and Central Africa Republic. However, even in areas without car-pet viper bites (0%) our results demonstrate that antivenoms remain highly cost-effective.

The combination of effective and relatively inexpensive antivenoms and the utilization of acheap, dependable and simple point-of-care test have been instrumental to our results. Anti-venom effectiveness is loosely inversely related to the ICER per DALY saved (Fig 2) [33]. Withdiscontinuation of production of geographically appropriate effective antivenoms and market-ing of inappropriate ineffective products the cost per DALY saved will substantially soar[32,39,40]. The 20WBCT is discriminatory and will be useful following envenoming fromother snakes in the rest of Africa that result in coagulopathy e.g., other species of carpet viper(Echis leucogaster, Echis pyramidum, Echis jogeri, Echis coloratus) and boomslang. In the

Fig 3. Monte Carlo Simulation showing the probability antivenom is cost-effective in majority of iterations (out of 10,000) for 4 countries withrespective Willingness To Pay (GDP/capita) and probabilities: top panel Chad (WTP $1035; prob-99.13%) [L] and Liberia (WTP $414; prob-97.28%)[R] and bottom panel Niger (WTP $385; prob-98.64%) [L] and Togo (WTP $589; prob-98.86%) [R].




context of differing circumstances where multiple types of snakes with varying manifestationsof envenoming or lack of reliable cheap differentiating test, antivenoms may not be as cost-effective. Nevertheless, where patients come along with the dead snakes, decision on antivenomchoice is feasible [23] and in such cases the differentiating test becomes not so useful. In theface of competing health needs and constrained-resources, it would be helpful to contextualizeour findings in the light of other healthcare initiatives. The cost-effectiveness of Human Immu-nodeficiency Virus treatment used in similar resource-constrained settings as first-line, sec-ond-line or for protecting negative partners among discordant partners ranged from US$530to US$1037 per year of life gained [33,55,56,57]. However, these estimates are still higher thanthe highest ICERs obtained for two countries in this analysis, i.e., Liberia and Sierra-Leonewith $257/DALY averted and $281/DALY averted respectively. The antivenom cost effective-ness is comparable to what obtains in other healthcare programmes. For example, the cost/DALY averted obtained in this study ranged from $100 to $200 for 7 countries (see Table 3)and is comparable to the cost effectiveness of rotavirus vaccines in other developing countriesin Africa and Asia [33,58,59]. Similarly, the cost/DALY averted in the remaining 7 countrieswas<$100/DALY averted and is similar to what obtains for preventing Human PapillomaVirus and pneumococcal infections with vaccines in West Africa [33,60,61].

We estimated a cost/DALY averted ranging from $73 in Benin to $247 in Sierra Leone if thecost input of antivenom is reduced to $125 per dose as obtained in Mali [30]. Doubling the costof antivenom for patients requiring more than a dose still yielded ICERs that remain cost effec-tive ranging from $136/DALY averted in Benin to $464/DALY averted in Sierra Leone.

In 8 of the 16 countries with neither indigenous antivenom effectiveness data nor data fromadjacent countries, we used efficacy derived from a meta-analysis with data inputs from othercountries in the sub-region [22, 38].

The study has a number of limitations. First, the effectiveness of antivenom was derivedfrom observational studies rather than RCTs. Definitive placebo controlled trials of anti-venom are considered unethical and RCTs are unlikely to be conducted in the absence of asuitable comparator to antivenom. However, to reduce bias, improve data quality and validityof estimates, three investigators independently searched both English and French literatureand extracted data using a checklist for consistency. Secondly, we applied the estimated pro-tection conferred by antivenoms against carpet viper envenoming to the antivenoms used forother than carpet viper envenoming (except in Benin and Guinea Conakry with specific esti-mates), though this assumption was subsequently dropped in a scenario analysis where anti-venoms were assumed to be ineffective (0%) against non-carpet viper envenoming. Thirdly,the analysis mainly considered amputation as the major disability to the exclusion of otheranecdotal complications [7, 20, 43, 44]. Fourthly, in our model, antivenoms only conferredprotection against death—being a more objective and valid outcome. Fifthly, other benefitsof antivenom (e.g. speedier recovery) were not included in the model. Sixth, we used separateEAR risk inputs for EchiTab-G and EchiTab-Plus respectively [23] but could not discerntheir respective efficacy against mortality so the combined estimate of the two was used inBurkina Faso and Nigeria. Lastly, we did not include the costs incurred for logistics in con-veying and preserving antivenoms as we assumed facilities for existing health programmeswill be utilized.

ConclusionThe findings from the cost effectiveness analysis demonstrate that providing and broadeningantivenom access throughout areas at risk in rural West Africa should be prioritized given theconsiderable reduction in deaths and disabilities that could be derived at a relatively small cost.



Author ContributionsConceived and designed the experiments: AGH AKMLMAI MBMMHDAW JPC. Performedthe experiments: AGH AKML. Analyzed the data: AGH AKMLMAI MBMMHDAW JPC.Contributed reagents/materials/analysis tools: AGH AKML. Wrote the paper: AGH AKMLMAI MBMMHDAW JPC.

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